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PMID:23752591

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Citation

Proserpio, V, Fittipaldi, R, Ryall, JG, Sartorelli, V and Caretti, G (2013) The methyltransferase SMYD3 mediates the recruitment of transcriptional cofactors at the myostatin and c-Met genes and regulates skeletal muscle atrophy. Genes Dev. 27:1299-312

Abstract

Elucidating the epigenetic mechanisms underlying muscle mass determination and skeletal muscle wasting holds the potential of identifying molecular pathways that constitute possible drug targets. Here, we report that the methyltransferase SMYD3 modulates myostatin and c-Met transcription in primary skeletal muscle cells and C2C12 myogenic cells. SMYD3 targets the myostatin and c-Met genes and participates in the recruitment of the bromodomain protein BRD4 to their regulatory regions through protein-protein interaction. By recruiting BRD4, SMYD3 favors chromatin engagement of the pause-release factor p-TEFb (positive transcription elongation factor) and elongation of Ser2-phosphorylated RNA polymerase II (PolIISer2P). Reducing SMYD3 decreases myostatin and c-Met transcription, thus protecting from glucocorticoid-induced myotube atrophy. Supporting functional relevance of the SMYD3/BRD4 interaction, BRD4 pharmacological blockade by the small molecule JQ1 prevents dexamethasone-induced myostatin and atrogene up-regulation and spares myotube atrophy. Importantly, in a mouse model of dexamethasone-induced skeletal muscle atrophy, SMYD3 depletion prevents muscle loss and fiber size decrease. These findings reveal a mechanistic link between SMYD3/BRD4-dependent transcriptional regulation, muscle mass determination, and skeletal muscle atrophy and further encourage testing of small molecules targeting specific epigenetic regulators in animal models of muscle wasting.

Links

PubMed PMC3690402 Online version:10.1101/gad.217240.113

Keywords

Animals; Cell Line; Cyclin-Dependent Kinase 9/metabolism; Dexamethasone/pharmacology; Histone-Lysine N-Methyltransferase/chemistry; Histone-Lysine N-Methyltransferase/deficiency; Histone-Lysine N-Methyltransferase/genetics; Histone-Lysine N-Methyltransferase/metabolism; Mice; Muscle Fibers, Skeletal/drug effects; Muscle Fibers, Skeletal/pathology; Muscle Proteins/genetics; Muscle, Skeletal/drug effects; Muscle, Skeletal/metabolism; Muscle, Skeletal/pathology; Muscular Atrophy/chemically induced; Muscular Atrophy/genetics; Myostatin/genetics; Nuclear Proteins/chemistry; Nuclear Proteins/metabolism; Phosphorylation; Phosphoserine/metabolism; Positive Transcriptional Elongation Factor B/metabolism; Protein Binding; Proto-Oncogene Proteins c-met/genetics; RNA Polymerase II/chemistry; RNA Polymerase II/metabolism; SKP Cullin F-Box Protein Ligases/genetics; Transcription Factors/chemistry; Transcription Factors/metabolism; Transcription, Genetic

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:EP300

enables

GO:0003682: chromatin binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:CDK9

part_of

GO:0008024: cyclin/CDK positive transcription elongation factor complex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:FBX32

acts_upstream_of_or_within

GO:0071549: cellular response to dexamethasone stimulus

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:SMYD3

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

PR:Q9ESU6
UniProtKB:O60885

F

Seeded From UniProt

complete

MOUSE:SMYD3

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:SMYD3

acts_upstream_of_or_within

GO:0033138: positive regulation of peptidyl-serine phosphorylation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:SMYD3

acts_upstream_of_or_within

GO:0014904: myotube cell development

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:SMYD3

acts_upstream_of_or_within

GO:0006469: negative regulation of protein kinase activity

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:SMYD3

acts_upstream_of_or_within

GO:0006334: nucleosome assembly

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:SMYD3

enables

GO:0000978: RNA polymerase II cis-regulatory region sequence-specific DNA binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:SMYD3

enables

GO:0000993: RNA polymerase II complex binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:SMYD3

enables

GO:0001162: RNA polymerase II intronic transcription regulatory region sequence-specific DNA binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:SMYD3

acts_upstream_of_or_within

GO:0045944: positive regulation of transcription by RNA polymerase II

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:SMYD3

acts_upstream_of_or_within

GO:0045184: establishment of protein localization

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:SMYD3

acts_upstream_of_or_within

GO:0071549: cellular response to dexamethasone stimulus

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:BRD4

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

PR:Q9CWR2

F

Seeded From UniProt

complete

MOUSE:BRD4

enables

GO:0003682: chromatin binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:BRD4

part_of

GO:0008024: cyclin/CDK positive transcription elongation factor complex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:GDF8

acts_upstream_of_or_within

GO:0071549: cellular response to dexamethasone stimulus

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:EP300

enables

GO:0000978: RNA polymerase II proximal promoter sequence-specific DNA binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:EP300

enables

GO:0097157: pre-mRNA intronic binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:TRI63

acts_upstream_of_or_within

GO:0071549: cellular response to dexamethasone stimulus

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

Notes

See also

References

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